Mutations matter in the intricate dance of determinants

Mutations in several genes contribute in differing degrees to the causation of PD. But the gene variants with the strongest influence are relatively rare, their impact differs greatly between populations, and environmental factors clearly also play a part in a complicated interaction.

A small number of gene mutations strongly predispose a person to develop Parkinson’s Disease (PD). Mutations of PARK8-LRRK2 or the gene encoding the lysosomal enzyme glucocerebrosidase (GBA) are examples. Mutations of genes like these may be necessary for the disease, but are generally not sufficient.

Inherent risk is modified by many other genetic factors with a relatively weak influence, such as are revealed by genome-wide association studies. Risk is also influenced by environmental factors. And by events such as the misfolding of alpha synuclein, which can occur as a sporadic event but may itself be environmentally or genetically driven.

The varying interaction of these influences gives rise to the range of PD phenotypes that we see. And the involvement of many factors may explain why – despite a strong genetic background – PD has a relatively late onset.

This was the model presented by Vincenzo Bonifati, of the Erasmus Medical Center in Rotterdam, the Netherlands, at the recent conference James Parkinson – An Essay on the Shaking Palsy 1817: A Celebration of 200 Years of Progress, organised by the International Parkinson and Movement Disorder Society (MDS).

The genetic architecture of PD differs between populations: two-thirds of Ashkenazi PD patients have variants of some PD-related gene

Proof of principle

The discovery of PARK1-alpha-synuclein proved the principle that there are monogenic forms of PD and strongly implicated the protein in pathogenesis. PARK8-LRRK2 mutations -- especially Gly2019Ser -- and variants of the GBA gene are examples of more frequent mutations with low penetrance overall that are strong risk factors for PD.

Up to 30% of people with GBA mutations develop PD by the age of eighty – which represents a 20-30% increase in lifetime risk. GBA mutations are also associated with Lewy body formation.

But the genetic architecture of PD varies between ethnic groups. Among the Ashkenazi Jewish population of Israel, who have a relatively homogeneous genetic pool, GBA L444P or N370S mutations were found in 15% of PD patients.1 This was true of only 3% of PD patients from other ethnic backgrounds. Even so, across sixteen co-operating centres worldwide, the presence of any GBA mutation increased the risk of PD five times. And, in terms of its frequency and potential as a therapeutic target, GBA is probably the most important PD-related gene yet discovered.

In frequency and potential as a therapeutic target, GBA is probably the most important PD-related gene yet discovered

GBA mutation is important in determining increased risk of PD but also influences the nature of the disease. In data published recently from a large Italian study, GBA mutation-carriers were more likely than non-carriers to have severe motor disease, and those with certain GBA mutations seemed more prone to develop dementia. 2 This was especially so for carriers of severe rather than mild GBA mutations.

A role for the environment

There are Parkinson’s-like conditions with a clear environmental cause such as encephalitis. There are examples of drug-induced Parkinsonian toxicity, notably that caused by MPTP and proteasome inhibitors; and there is continuing concern about the potential role of certain pesticides in PD itself.

A recent nationwide study in France related PD incidence at the cantonal level to agricultural activities varying in the intensity of pesticide use.3 People living in cantons with the greatest density of vineyards – where pesticide use is high – had a significantly higher PD risk. The strength of the association increased with age.

The recent MDS research criteria for prodromal PD attribute a likelihood ratio of 1.5 to regular pesticide exposure, and the same to occupational solvent exposure.

Environmental factors remain a possibility, Dr Bonifati said, though association does not equal cause. Geographical clusters of patients with Parkinsonian symptoms have been identified in Guam and Guadalupe.

The one relevant lifestyle factor that has been clearly established is protective: in smokers, the risk of PD is halved. That is not because of the censoring effect of mortality; and the underlying mechanism has not been confirmed. But it could relate to the fact that smoking is a potent inhibitor of monoamine oxidases.

Our “other genome”

In considering genetic factors, we must also note that there also the genes of the gut microbiome, with which the host genome interacts. Even if the gut microbiome is different in PD patients, the association is not necessarily causal. It could be the effect of confounding factors such as exposure to therapeutic drugs. But the intestinal microbiome could be highly relevant if we confirm the hypothesis that PD starts in the gut. And we cannot ignore the hypothesis that misfolded alpha-synuclein acts as a template for normal synuclein, leading to prion-like spread from bowel to brain.

Tau, which may also be a prion-like protein, is another potential factor. But it does not emerge from all GWAS studies (in Japanese patients, for example) and so is not a primary influence.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

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